Implantable device for controlled, extended delivery of parathyroid hormone

ABSTRACT

Method and devices are provided for extended and controlled delivery of parathyroid hormone to a patient. The method includes implanting a medical device into the patient, the medical device comprising a substrate, a plurality of reservoirs in the substrate, a release system contained in each of the reservoirs, wherein the release system comprises parathyroid hormone; and controllably releasing a pharmaceutically effective amount of the parathyroid hormone from the reservoirs. The parathyroid hormone can be released intermittently, such as once daily over an extended period (e.g., two months, ten months, or more.). The device can further include reservoirs containing a bone resorption inhibitor or other drug for release. The devices are useful in delivering PTH for the treatment and prevention of bone loss, such as associated with osteoporosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/654,761, filed Sep. 4, 2003, which claims the benefit of U.S.Provisional Application No. 60/408,165, filed Sep. 4, 2002. Theapplications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention is generally in the field of methods and devices for thecontrolled delivery of parathyroid hormone (PTH) to patients, forexample, to promote the growth and maintenance of bone tissue.

The mechanism of bone loss is not completely understood, but thedisorder effectively arises from an imbalance in the formation of newhealthy bone and the resorption of old bone. The bone loss includes adecrease in both mineral content and protein matrix components of thebone, and leads to an increased rate of bone fracture. These fractures,predominantly femoral bones and bones in the forearm and vertebrae, leadto an increase in general morbidity and a loss of stature and mobility,as well as an increase, in many cases, in mortality caused bycomplications from the fracture.

Bone loss occurs, for example, in post-menopausal women, patients whohave undergone hysterectomy, patients undergoing or who have undergonelong-term administration of corticosteroids, patients suffering fromCushing's syndrome, and patients having gonadal dysgenesis. Uncheckedbone loss can lead to osteoporosis, a major debilitating disease whoseprominent feature is the loss of bone mass (decreased density andenlargement of bone spaces) without a reduction in bone volume,producing porosity and fragility. Post-menopausal osteoporosis isassociated with the large and rapid loss of bone mass due to thecessation of estrogen production by the ovaries. One source reports thatten million individuals in the United States are estimated to alreadyhave osteoporosis and almost 34 million more are estimated to have lowbone mass, placing them at increased risk for the disease, and that oneout of two women and one in eight men over age 50 will have anosteoporosis-related fracture in their lifetime.

PTH is involved in calcium and skeletal homeostasis. It stimulates thetubular resorption of calcium by the kidney and inhibits thereabsorption of phosphate and bicarbonate by the proximal renal tubules.PTH also affects the kidney by stimulating production of a vitamin Dmetabolite (1,25(OH)2D), which is an in vivo stimulator of osteoclastsand an enhancer of intestinal calcium absorption. The increase inintestinal calcium absorption following PTH stimulation is mediated bythis vitamin D metabolite. In vivo, PTH stimulates osteoclastic boneresorption with the release of calcium into the circulation, and causesproliferation of osteoblasts.

With the general understanding of bone growth and its regulation,various approaches have been proposed to treat diseases involvingreduction of bone mass and accompanying disorders by the administrationof bone resorption inhibitors and/or anabolic agents, such as PTH.Examples of such approaches include U.S. Pat. No. 6,239,144 to Galvin etal., which discloses treating conditions associated with a lack of PTHby administering a compound having activity as a tachykinin receptorantagonist, which reportedly can increase the secretion of PTH; U.S.Pat. No. 5,670,514 to Audia et al., which discloses inhibiting bone lossby the administration of a 5α-reductase inhibitor (abenzoquinolin-3-one), alone or in combination with another bone anabolicagent, such as PTH; and U.S. Pat. No. 5,510,370 to Hock, which disclosestreatment of bone loss in a patient by administering PTH sequentially,concurrently, or simultaneously with raloxifene.

It has been established that low dose, intermittent administration ofPTH is associated with anabolic effects in humans, whereas higher dose,continuous administration of PTH is associated with catabolic effects.Rubin & Bilezikian, Int. J. Fertil. 47(3):103-15 (2002); Schaefer,Novartis Found Symp 227:225-39 (2000). U.S. Pat. No. 6,239,144 disclosesthat there is a dose dependent stimulation of the mineral appositionrate by PTH and that the result of the administration of PTH on skeletalhomeostasis depends on how the hormone is administered. For the samedaily dose, the bone volume shows a dose dependent increase if the dailydose of the hormone is given as one single injection. However, when thesame daily dose is administered by continuous infusion with asubcutaneous mini-osmotic pump, the result is bone loss. Intermittentinjection causes practically no effect on the serum calcium levels,whereas infusion causes a dose dependent increase in the serum calcium.The effects of PTH administered by these two routes on bone mineralapposition rate appeared to be the same. Once-daily injections are anundesirable means for the treatment and prevention of bone loss, becausetreatment and/or prophylaxis must occur over an extended period andfrequent injections would be objectionable and would discourage patientcompliance with the treatment. It would thus be desirable to providealternative means for administering PTH intermittently, alone or incombination with other drugs useful in promoting bone growth and/orinhibiting bone loss.

There are myriad technologies generally referred to as providingcontrolled or sustained drug delivery, which deliver drug by a varietyof routes. Although some controlled release methods and devices havebeen somewhat effective in controlling protein or peptide delivery inthe body, several limitations can influence their suitability orpracticality for administering a particular therapeutic agent, such asPTH. For example, many “controlled” release drug delivery systems maynot provide a well-defined release profile. Other technologies may besuitable for continuous release (e.g., an ALZET™ osmotic pump), but notpulsatile release. Yet other technologies that are suitable for deliveryof small molecule drugs would be unsuitable for long-term storage anddelivery of fragile protein or peptide drug molecules. Such moleculesmay, for example, undergo degradation and denaturation associated withexposure to moisture, elevated temperatures (e.g., 37° C.), and/or byother means. Still other drug delivery systems undesirably would requireperiodic (frequent) replacement or refilling, or an unacceptably largesize in order to provide for the administration of drug for long-termtherapy.

It therefore would be desirable to provide a drug delivery systemcapable of accurately delivering a therapeutically and/orprophylactically effective amount of PTH, alone or in combination withother drugs. It desirably would provide well-defined pulsatile releaseof PTH over an extended period of time in a small, anatomicallyacceptable configuration, without requiring refilling of the deliverydevice with drug, repeated injections, or repeated replacement of partor the entire device over the course of treatment. In addition, it wouldbe desirable for the drug delivery rate to be adjustable over the courseof treatment.

SUMMARY OF THE INVENTION

Method and devices are provided for extended and controlled delivery ofparathyroid hormone to a patient, for example, for the treatment andprevention of bone loss, such as associated with osteoporosis.

In one aspect, the method includes implanting a medical device into thepatient, the medical device comprising a substrate, a plurality ofreservoirs in the substrate, a release system contained in each of thereservoirs, wherein the release system comprises parathyroid hormone;and controllably releasing a pharmaceutically effective amount of theparathyroid hormone from the reservoirs.

In one embodiment of the method, the step of controllably releasingprovides intermittent release of the parathyroid hormone. In oneembodiment, the parathyroid hormone is released in a pulsatile manner,each pulse having a duration of less than four hours.

In one embodiment of the method, the parathyroid hormone is releaseddaily in intermittent doses of between about 10 and 300 μg. In oneembodiment, the daily intermittent doses are released over a period often months or more.

In one embodiment of the method, the pharmaceutically effective amountof the parathyroid hormone, released over a first period of time, iseffective to form bone tissue. In another embodiment, the method furtherincludes releasing a pharmaceutically effective amount of a boneresorption inhibitor, released over a second period of time, to maintainbone tissue at a level present after the first period of time. In oneembodiment, the bone resorption inhibitor is selected from the groupconsisting of bisphosphonates, selective estrogen receptor modulators,calcitonins, vitamin D analogs, and calcium salts.

In another aspect, the implantable device for the extended, controlleddelivery of parathyroid hormone to a patient comprises a substrate, aplurality of reservoirs in the substrate, a release system contained ineach of the reservoirs, wherein the release system comprises parathyroidhormone, and a control means for selectively releasing apharmaceutically effective amount of the parathyroid hormone from eachof the reservoirs. In one embodiment, the device releases apharmaceutically effective amount of parathyroid hormone once daily overa period of at least six months.

In one embodiment, the device further includes at least one reservoirwhich contains a second release system comprising a drug other thanparathyroid hormone. For example, the drug could be an anti-resorptiveagent.

In one embodiment of the device, each of the reservoirs contains betweenabout 10 and 40 μg of parathyroid hormone for release.

In one embodiment, the device includes 300 or more reservoirs, eachcontaining a release system comprising parathyroid hormone.

In one embodiment of the device, the release system comprisesparathyroid hormone in combination with a pharmaceutically acceptableexcipient. For example, the release system could include parathyroidhormone suspended in a non-aqueous vehicle. As another example, the PTHcould be dried or lyophilized with an excipient that promotesre-dissolution upon release. Such an excipient could be for example,polyethylene glycol having a molecular weight between about 100 and10,000 Daltons.

In one embodiment of the device, the control means includes reservoircaps covering the release system of the reservoirs. In one embodiment,the control means further comprises means for actively disintegrating orpermeabilizing the reservoir caps. In one embodiment, the means foractively disintegrating comprises a power source for passing an electriccurrent or potential through the reservoir caps. In a specificembodiment, the reservoir caps comprise an electrically conductivematerial and are electrically connected to an electrical input lead andto an electrical output lead, and the means for actively disintegratingor permeabilizing the reservoir cap comprises means for selectivelyapplying an electrical current through the reservoir cap, via the inputlead and output lead, in an amount effective to locally heat thereservoir cap to cause the reservoir cap to disintegrate to permitrelease of the parathyroid hormone. In another specific embodiment, themeans for actively disintegrating the reservoir cap comprises a cathode,a microprocessor, a timer, and a demultiplexer, and wherein thereservoir caps each comprise an anode and upon application of anelectric potential between the cathode and anode the reservoir capdisintegrates to permit release of the parathyroid hormone.

In one embodiment, the device includes a sensor, such as one thatmeasures plasma calcium.

In another embodiment, the control means comprises two or more layers ofrelease system having different compositions. Such an embodiment caneffectively provide a passive control system for effecting pulsatilerelease.

In one embodiment, the device is capable of vaginal transmucosaladministration of the parathyroid hormone. For example, the device cancomprise a ring-shaped or rod-shaped body for fitting engagement withinthe vagina.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of one embodiment of an implantableactive-release microchip device for delivery of parathyroid hormone.

FIG. 2 is a perspective view of another embodiment of an implantableactive-release microchip device for delivery of parathyroid hormone.

FIG. 3 is a cross-sectional view of one embodiment of a passive releasemicrochip device for delivery of parathyroid hormone.

FIGS. 4A and 4B are cross-sectional views of two of the many possibleembodiments of substrate/reservoir geometries: straight walledreservoirs (FIG. 4A) and combination straight and tapered walledreservoirs (FIG. 4B).

FIG. 5 is a cross-sectional view of one embodiment of a passive releasedevice substrate having a layered release system for controlling releaseas well as for controlling aggregation and precipitation of PTH.

FIG. 6 is a plan view of one embodiment of the medical device describedherein for intravaginal delivery of PTH.

FIG. 7 is a cross-sectional view of the device shown in FIG. 6.

DETAILED DESCRIPTION OF THE INVENTION

Implantable medical devices have been developed for the controlleddelivery of parathyroid hormone. The device comprises a substratecomprising a plurality of reservoirs; a release system comprisingparathyroid hormone contained in the reservoirs; and a means forcontrollably releasing a pharmaceutically effective amount of theparathyroid hormone from the reservoirs.

In one embodiment, the medical device comprises a microchip device. Asused herein, a “microchip” is a miniaturized device fabricated usingmethods described in U.S. Pat. No. 5,797,898 and No. 6,123,861, toSantini, Jr. et al., as well as other methods commonly applied to themanufacture of integrated circuits and MEMS (MicroElectroMechanicalSystems) such as ultraviolet (UV) photolithography, reactive ionetching, and electron beam evaporation, as known in the art, as well asMEMS methods that are not standard in making computer microchips,including those described, for example, in PCT WO 01/41736 and Madou,Fundamentals of Microfabrication (CRC Press, 1997), and othermicromolding and micromachining and polymer forming techniques known inthe art.

As used herein, the terms “comprise,” “comprising,” “include,” and“including” are intended to be open, non-limiting terms, unless thecontrary is expressly indicated.

I. Device Components and Materials

The device includes a substrate having a plurality of reservoirs, whichcontain the PTH and, optionally, other drug molecules. The substrate,reservoirs, reservoir caps, control circuitry, and power source aredescribed at least in part herein and/or in U.S. Pat. No. 5,797,898, No.6,123,861, No. 6,551,838, No. 6,491,666, and No. 6,527,762, as well asU.S. Patent Application Publications No. 2002/0138067, No. 2002/0072784,No. 2002/0151776, and No. 2002/0107470. In one embodiment, control ofreservoir cap opening includes electro-thermal ablation techniques, asdescribed in U.S. Pat. No. 7,455,667, which is incorporated herein byreference.

The Substrate and Reservoirs

The substrate is the structural body (e.g., part of a device) in whichthe reservoirs are formed, e.g., it contains the etched, machined, ormolded reservoirs. A reservoir is a well, a container. MEMS methods,micromolding, and micromachining techniques known in the art can be usedto fabricate the substrate/reservoirs from a variety of materials. See,for example, U.S. Pat. No. 6,123,861 and U.S. Patent ApplicationPublication No. 2002/0107470. Examples of suitable substrate materialsinclude metals, ceramics, semiconductors, and degradable andnon-degradable polymers. Biocompatibility of the substrate materialtypically is preferred for in vivo device applications. The substrate,or portions thereof, may be coated, encapsulated, or otherwise containedin a biocompatible material (e.g., poly(ethylene glycol),polytetrafluoroethylene-like materials, inert ceramics, titanium, andthe like) before use.

The substrate can be flexible or rigid. In one embodiment, the substrateserves as the support for a microchip device. In one example, thesubstrate is formed of silicon.

The substrate can have a variety of shapes, or shaped surfaces. It can,for example, have a release side (i.e., an area having reservoir caps)that is planar or curved. The substrate may, for example, be in a shapeselected from disks, cylinders, or spheres. In one embodiment, therelease side can be shaped to conform to a curved tissue surface or intoa body lumen. In another embodiment, the back side (distal the releaseside) is shaped to conform to an attachment surface.

The substrate may consist of only one material, or may be a composite ormulti-laminate material, that is, composed of several layers of the sameor different substrate materials that are bonded together.

In one embodiment, the substrate is hermetic, that is impermeable (atleast during the time of use of the reservoir device) to the moleculesto be delivered and to surrounding gases or fluids (e.g., water, blood,electrolytes or other solutions).

In another embodiment, the substrate is made of a strong material thatdegrades or dissolves over a defined period of time into biocompatiblecomponents. Examples of biocompatible polymers include poly(lacticacid)s, poly(glycolic acid)s, and poly(lactic-co-glycolic acid)s, aswell as degradable poly(anhydride-co-imides).

The substrate thickness can vary depending upon the particular deviceand application using the activation system described herein. Forexample, the thickness of a device may vary from approximately 10 μm toseveral millimeters (e.g., 500 μm). Total substrate thickness andreservoir volume can be increased by bonding or attaching wafers orlayers of substrate materials together. The device thickness may affectthe volume of each reservoir and/or may affect the maximum number ofreservoirs that can be incorporated onto a substrate. The size andnumber of substrates and reservoirs can be selected to accommodate thequantity and volume of reservoir contents needed for a particularapplication, although other constraints such as manufacturinglimitations or total device size limitations (e.g., for implantationinto a patient) also may come into play. For example, devices for invivo applications desirably would be small enough to be implanted usingminimally invasive procedures. Alternatively, the device would beappropriately sized to be inserted into the vagina for intravaginaladministration of PTH.

The substrate includes at least two and preferably tens or hundreds ofreservoirs. For example, one reservoir could be provided for each dailydose of PTH required, for example, over a 6-, 8-, 10-, or 12-monthcourse of treatment. The substrate could include, for example, 300 to400 reservoirs, each containing a release system comprising parathyroidhormone.

In one embodiment, the reservoir has a volume equal to or less than 500μL (e.g., less than 250 μL, less than 100 μL, less than 50 μL, less than25 μL, less than 10 μL, etc.) and greater than about 1 mL (e.g., greaterthan 5 mL, greater than 10 mL, greater than about 25 mL, greater thanabout 50 mL, greater than about 1 μL, etc.).

Two of the many possible embodiments of substrate/reservoir geometriesare illustrated in FIGS. 4A-4B. The embodiment shown in FIG. 4A showssubstrate 45 having reservoirs 46 a and 46 b, which are covered byreservoir caps 47 a and 47 b, respectively. Reservoirs 46 a and 46 bhave straight, i.e. non-tapered, walls. The embodiment shown in FIG. 4Bshows a laminate substrate, composed of lower portion 45 a and upperportion 45 b, which has reservoirs 48 a and 48 b, which are covered byreservoir caps 47 a and 47 b, respectively. Reservoirs 48 a and 48 bhave a combination of straight walls in the lower portion 45 a of thesubstrate and tapered walls in the upper portion 45 b of the substrate.

Drug and Release System

The release system comprises a pharmaceutical formulation of theparathyroid hormone. As used herein, “release system” includes thesituations where the PTH molecules are in pure form (e.g., as alyophilized powder), in suspension, in solution, or in a matrix formedof biodegradable material or another material which releasesincorporated PTH molecules by diffusion or disintegration of the matrix.The release system can, for example, include excipients that modulatethe rate of release of PTH.

Parathyroid Hormone

As used herein, the term “parathyroid hormone” or “PTH” includes thecomplete human hormone (hPTH 1-84); fragments of the hormone responsiblefor bone growth promotion, such as hPTH 1-34 and hPTH 1-38, and analogsin which the amino acid sequence is modified slightly, yet retain bonegrowth promotion properties, such as PTH-RP; and synthetic and/orrecombinant biologically active peptide derivatives of parathyroidhormone (e.g., hPTH(1-28)), such as described in U.S. Pat. No. 6,417,333to Bringhurst et al. The PTH may be native or synthesized by chemical orrecombinant means.

The PTH may or may not be in lyophilized form, depending upon thedesired formulation and storage requirements. For example, the PTH couldbe provided in a lyophilized salt form, such as a chloride or acetate(e.g., as hPTH(1-34)Cl or PTH(1-34)OAc), which could be sealed in thereservoirs under nitrogen gas with low water content, without excipient.Alternatively, lyophilized PTH can be suspended in a non-solvent (e.g.,non-aqueous) vehicle. In another embodiment, the PTH can be incorporatedinto micelles or liposomes.

In one embodiment, the release system comprises PTH dried or lyophilizedwith an excipient that promotes re-dissolution upon release. Such acomposition would accelerate the rate of release (i.e., reduce the pulseduration). An example of a suitable excipient in this embodiment ispolyethylene glycol having a molecular weight between about 100 and10,000 Daltons.

Excipient

In one embodiment, the release system includes PTH in (e.g., in amixture with) a pharmaceutically acceptable excipient. As used herein,the term “excipient” is used broadly to include virtually any suitabledrug delivery vehicle.

The excipient may be a solvent or non-solvent for the PTH to prepare asolution or suspension of the PTH, respectively. The solvent ornon-solvent may be aqueous or non-aqueous, so long as the PTH issubstantially stable in the solution or suspension during storage in thereservoirs of the drug delivery device and for the useful lifetime ofthe device.

In one embodiment, the PTH is provided in suspension with a non-aqueousvehicle suitable for stable storage. Preferred pharmaceuticallyacceptable excipients include non-aqueous vehicles suitable forsuspension and stable storage of PTH at 37° C. for several months,preferably a year or more. The non-aqueous vehicle could be ananhydrous, aprotic, hydrophobic, non-polar liquid, with low reactivityto PTH. Representative examples of non-aqueous vehicles includebiocompatible perhalohydrocarbons or unsubstituted saturatedhydrocarbons. Examples of these include perfluorodecalin,perfluorobutylamine, perfluorotripropylamine,perfluoro-N-methyldecahydroquindine, perfluoro-octohydroquinolidine,perfluoro-N-cyclohexylpyrilidine, perfluoro-N,N-dimethylcyclohexylmethylamine, perfluoro-dimethyl-adamantane, perfluorotri-methylbicyclo(3.3.1) nonane, bis(perfluorohexyl)ethene, bis(perfluorobutyl)ethene,perfluoro-1-butyl-2-hexyl ethene, tetradecane, methoxyflurane andmineral oil. See, e.g., U.S. Pat. No. 6,264,990 to Knepp et al.

In one embodiment, the PTH is provided in a solution. An example of anon-aqueous (anhydrous) solvent that may be suitable is DMSO (dimethylsulfoxide).

In another embodiment, the release system comprises PTH dried orlyophilized with an excipient that would promote re-dissolution uponrelease, such as polyethylene glycol having a molecular weight betweenabout 100 and 10,000 Daltons.

Other suitable pharmaceutically acceptable excipients include variouscarriers approved for parenteral administration, including saline,Ringer's solution, Hank's solution, and solutions of glucose, lactose,dextrose, mannitol, ethanol, glycerol, albumin, and the like. Therelease system may optionally include stabilizers, antioxidants,antimicrobials, preservatives, buffering agents, surfactants,dessicants, and other additives useful for storing and releasing PTHfrom the reservoirs in vivo.

PTH Dosage

The devices can be used to deliver essentially any medically indicateddosage of PTH. In one embodiment, PTH dosages are between 0.5 and 1.0μg/(kg·day). In one embodiment, the PTH advantageously is released indaily pulsatile doses of between 10 and 300 μg. For example, eachreservoir could contain a single dose, e.g., about 20 μg PTH (1-34) orabout 100 to 200 μg PTH (1-84) in a suitable formulation. Releasedosages can be varied by a number of techniques, for example, byproviding different quantities of drug among different reservoirs (somereservoirs contain 20 μg of PTH, and others contain 10, 15, or 40 μg ofPTH) and/or by combining various numbers of reservoirs to form a singledose (e.g., simultaneously opening two reservoirs each containing 10 μgof PTH).

Other Drugs

While at least two of the reservoirs (and more likely tens to hundredsof reservoirs) will contain PTH, reservoirs may contain release systemconsisting or comprising other (non-PTH) drugs for release. Theseadditional drugs may be in the same reservoirs as the PTH or indifferent reservoirs. Representative examples of these other drugsinclude bone resorption inhibitors, such as bisphosphonates (e.g.,alendronate, risedronate sodium), estrogen, selective estrogen receptormodulators (e.g., raloxifene HCl), calcitonins, vitamin D analogs, andcalcium salts. In an alternative embodiment of the method foradministering PTH, the PTH is delivered (e.g., subcutaneously orintravaginally) from the implanted medical device described herein andthe other drug, e.g., an anti-resorptive agent, is administered orallyusing a conventional oral dosage form. In either approach (other drugadministered from implanted device or orally), the PTH and the otherdrug(s) may be administered sequentially, concurrently, orsimultaneously.

These other drugs, alone or in combination with a pharmaceuticallyacceptable excipient, may be in pure solid, liquid (e.g., solution orsuspension), or gel form, or mixed with other materials that affect therelease rate and/or time. The drugs may be in the form of solid mixturesincluding amorphous and crystalline mixed powders, monolithic solidmixtures, lyophilized powders, and solid interpenetrating networks. Thedrugs may, for example, be in the form of liquid mixtures, includingsolutions, emulsions, colloidal suspensions, and slurries, or in theform of gel mixtures, including hydrogels.

Reservoir Caps

As used herein, the term “reservoir cap” includes a membrane or otherstructure suitable for separating the contents of a reservoir from theenvironment outside of the reservoir. It generally is self-supportingacross the reservoir opening, although caps having additional structuresto provide mechanical support to the cap can be fabricated. Selectivelyremoving the reservoir cap or making it permeable will then “expose” thecontents of the reservoir to the environment (or selected componentsthereof) surrounding the reservoir. In preferred embodiments, thereservoir cap is selectively disintegrated. As used herein, the term“disintegrate” is used broadly to include without limitation degrading,dissolving, rupturing, fracturing or some other form of mechanicalfailure, as well as a loss of structural integrity due to a chemicalreaction (e.g., electrochemical degradation) or phase change (e.g.,melting) in response to a change in temperature, unless a specific oneof these mechanisms is indicated. In one specific embodiment, the“disintegration” is by an electrochemical activation technique, such asdescribed in U.S. Pat. No. 5,797,898. In another specific embodiment,the “disintegration” is by an electro-thermal ablation technique, suchas described in U.S. Pat. No. 7,455,667.

In active release devices, the reservoir cap generally includes anymaterial that can be disintegrated or permeabilized in response to anapplied stimulus, e.g., electric field or current, magnetic field,change in pH, or by thermal, chemical, electrochemical, or mechanicalmeans.

In one embodiment, the reservoir cap is a thin metal film and isimpermeable to the surrounding environment (e.g., body fluids or anotherchloride containing solution). In one variation, a particular electricpotential is applied to the metal reservoir cap, which is then oxidizedand disintegrated by an electrochemical reaction, to release the drugfrom the reservoir. Examples of suitable reservoir cap materials includegold, silver, copper, and zinc.

In another variation, the reservoir cap is heated (e.g., using resistiveheating) to cause the reservoir cap to melt and be displaced from thereservoir to open it. This latter variation could be used, for example,with reservoir caps formed of a metal or a non-metal material, e.g., apolymer. In yet another variation, the reservoir cap is formed of apolymer or other material that undergoes a temperature-dependent changein permeability such that upon heating to a pre-selected temperature,the reservoir is rendered permeable to the drug and bodily fluids topermit the drug to be released from the reservoir through the reservoircap.

In still another embodiment, the reservoir cap is formed of a conductivematerial, such as a metal film, through which an electrical current canbe passed to electrothermally ablate it, as described in U.S. Pat. No.7,455,667. Representative examples of suitable reservoir cap materialsinclude gold, copper, aluminum, silver, platinum, titanium, palladium,various alloys (e.g., Au/Si, Au/Ge, Pt—Ir, Ni—Ti, Pt—Si, SS 304, SS316), and silicon doped with an impurity to increase electricalconductivity, as known in the art. In one embodiment, the reservoir capis in the form of a thin metal film. In one embodiment, the reservoircap is part of a multiple layer structure, for example, the reservoircap can be made of multiple metal layers, such as a multi-layer/laminatestructure of platinum/titanium/platinum. The reservoir cap is operably(i.e. electrically) connected to an electrical input lead and to anelectrical output lead, to facilitate flow of an electrical currentthrough the reservoir cap. When an effective amount of an electricalcurrent is applied through the leads and reservoir cap, the temperatureof the reservoir cap is locally increased due to resistive heating, andthe heat generated within the reservoir cap increases the temperaturesufficiently to cause the reservoir cap to be electrothermally ablated(i.e., ruptured).

In passive release devices, the reservoir cap is formed from a materialor mixture of materials that degrade, dissolve, or disintegrate overtime, or that do not degrade, dissolve, or disintegrate, but arepermeable or become permeable to molecules or energy. Representativeexamples of reservoir cap materials include polymeric materials, andnon-polymeric materials such as porous forms of metals, semiconductors,and ceramics. Passive semiconductor reservoir cap materials includenanoporous or microporous silicon membranes.

In one embodiment, the release system containing the molecules to bedelivered is covered by a degradable cap material that is nearlyimpermeable to the molecules. The time of release of the molecules fromthe reservoir will be limited by the time necessary for the cap materialto degrade or dissolve. In another embodiment, the cap material isnon-degradable and is permeable to the molecules to be delivered. Thephysical properties of the material used, its degree of crosslinking,and its thickness will determine the time necessary for the molecules todiffuse through the cap material. If diffusion out of the release systemis limiting, the cap material delays the onset of release. If diffusionthrough the cap material is limiting, the cap material determines therelease rate of the molecules in addition to delaying the onset ofrelease.

In one embodiment, a passive, layered release system to providepulsatile release is used in combination with an actuatable reservoircap.

FIG. 3 illustrates a microchip device for the passive release ofparathyroid hormone. It shows device 40 which includes substrate 41having three reservoirs 42 a, 42 b, and 42 c, which contain,respectively, release system 43 a, 43 b, and 43 c, which are coveredrespectively, by bioerodible or biodegradable reservoir caps 44 a, 44 b,and 44 c. In this embodiment, the thickness of the reservoir caps isdifferent for each reservoir cap to provide different times of PTHrelease.

Any combination of passive and/or active release reservoir cap can bepresent in a single microchip device. For example, the reservoir cap canbe removed by electrothermal ablation to expose a passive release systemthat only begins its passive release after the reservoir cap has beenactively removed. Alternatively, a given substrate can include bothpassive and active release reservoirs.

Controlling Release

The device preferably is provided with a control means to control thetime at which the PTH or other drug is released from the device, andinto the patient's body. At least for PTH, the control means shouldprovide intermittent release, for example, daily over a period of months(e.g., 2, 6, 10, or preferably 12, months or more). The particularfeatures of the control means depend on the mechanism of reservoir capactivation described herein.

For example, the control means can include the hardware, electricalcomponents, and software needed to control and deliver the electriccurrent from a power source to selected reservoir caps for actuation(i.e., opening). The control means can include an input source, amicroprocessor, a timer, a demultiplexer (or multiplexer), and a powersource. As used herein, the term “demultiplexer” also refers tomultiplexers. The power source provides energy to activate the selectedreservoir, i.e. trigger release of drug from the particular reservoirdesired for a given dose. For example, the operation of the reservoiropening system can be controlled by an on-board microprocessor (e.g.,the microprocessor is within an implantable or insertable device). Themicroprocessor can be programmed to initiate the disintegration orpermeabilization of the reservoir cap in response at a pre-selected timeor in response to one or more of signals or measured parameters,including receipt of a signal from another device (for example by remotecontrol or wireless methods) or detection of a particular conditionusing a sensor such as a biosensor. In another embodiment, a simplestate machine is used, as it typically is simpler, smaller, and/or usesless power than a microprocessor. The device can also be activated orpowered using wireless means, for example, as described in U.S.20020072784 A1 to Sheppard et al.

In one embodiment, the device includes a substrate having atwo-dimensional array of reservoirs arranged therein, a release systemcomprising PTH contained in the reservoirs, anode reservoir capscovering each of the reservoirs, cathodes positioned on the substratenear the anodes, and means for actively controlling disintegration ofthe reservoir caps. The means includes a power source and circuitry tocontrol and deliver an electrical potential energy drives a reactionbetween selected anodes and cathodes. Upon application of a potentialbetween the electrodes, electrons pass from the anode to the cathodethrough the external circuit causing the anode material (reservoir cap)to oxidize and dissolve into the surrounding fluids, exposing therelease system containing the PTH for delivery to the surroundingfluids, e.g., in vivo. The microprocessor directs power to specificelectrode pairs through a demultiplexer as directed by a PROM, remotecontrol, or biosensor.

In another embodiment, the activation energy initiates a thermallydriven rupturing or permeabilization process, for example, as describedin PCT WO 01/12157. For example, the means for controlling release canactively disintegrate or permeabilize a reservoir cap using a resistiveheater. The resistive heater can cause the reservoir cap to undergo aphase change or fracture, for example, as a result of thermal expansionof the reservoir cap or release system, thereby rupturing the reservoircap and releasing the PTH from the selected reservoir. The applicationof electric current to the resistor can be delivered and controlledusing components as described above for use in the electrochemicaldisintegration embodiment. For example, a microprocessor can directcurrent to select reservoirs at desired intervals.

In yet another embodiment, control means controls electro-resistiveablation of the reservoir cap. For example, the drug delivery devicecould include a reservoir cap formed of an electrically conductivematerial, which prevents the PTH from passing out from the device; anelectrical input lead connected to the reservoir cap; an electricaloutput lead connected to the reservoir cap; and a control means todeliver an effective amount of electrical current through the reservoircap, via the input lead and output lead, to locally heat and rupture thereservoir cap to release the PTH. In one embodiment, the reservoir capand conductive leads are formed of the same material, where thetemperature of the reservoir cap increases locally under applied currentbecause the reservoir cap is suspended in a medium that is lessthermally conductive than the substrate. Alternatively, the reservoircap and conductive leads are formed of the same material, and thereservoir cap has a smaller cross-sectional area in the direction ofelectric current flow, where the increase in current density through thereservoir cap causes an increase in localized heating. The reservoir capalternatively can be formed of a material that is different from thematerial forming the leads, wherein the material forming the reservoircap has a different electrical resistivity, thermal diffusivity, thermalconductivity, and/or a lower melting temperature than the materialforming the leads. Various combinations of these embodiments can beemployed.

Microelectronic device packages are typically made of an insulating ordielectric material such as aluminum oxide or silicon nitride. Low costpackages can also be made of plastics or reinforced epoxies (similar tothose used in making printed circuit boards). Their purpose is to allowall components of the device to be placed in close proximity and tofacilitate the interconnection of components to power sources and toeach other, while protecting the electronics from the environment.Implanted microchip device packages will need to be hermetically sealed,e.g., in a titanium encasement, which essentially exposes only thereservoir caps.

The control means can include a microprocessor, a timer, ademultiplexer, and an input source (for example, a memory source, asignal receiver, or a biosensor), and a power source. The timer anddemultiplexer circuitry can be designed and incorporated directly ontothe surface of the microchip during electrode fabrication, or may beincorporated in a separate microchip. The criteria for selection of amicroprocessor are small size, low power requirement, and the ability totranslate the output from memory sources, signal receivers, orbiosensors into an address for the direction of power through thedemultiplexer to a specific reservoir on the microchip device. Selectionof a source of input to the microprocessor such as memory sources,signal receivers, or biosensors depends on the microchip device'sparticular application and whether device operation is preprogrammed,controlled by remote means, or controlled by feedback from itsenvironment (i.e. biofeedback).

A microprocessor is used in conjunction with a source of memory such aserasable programmable read only memory (EPROM), a timer, ademultiplexer, and a power source such as a battery or a biofuel cell. Aprogrammed sequence of events including the time a reservoir is to beopened and the location or address of the reservoir is stored into theEPROM by the user. When the time for exposure or release has beenreached as indicated by the timer, the microprocessor sends a signalcorresponding to the address (location) of a particular reservoir to thedemultiplexer. The demultiplexer routes an input, such as an electricpotential or current, to the reservoir addressed by the microprocessor.

In one embodiment of a passive release embodiment, the means forcontrollably releasing comprises the release system having differentlayers of disintegratable materials such that pulsatile release of theparathyroid hormone is provided by disintegration of the layers. Forexample, a single pulse from each reservoir using multiple reservoirseffectively provides a pulsatile release profile. Alternatively, apulsatile release profile can be provided from a single reservoir, forexample, by incorporating several layers of a release system and othermaterials into a single reservoir. In either case, the reservoir capscan be formed from a material that degrades or dissolves over time, ordoes not degrade or dissolve, but is permeable to the PTH molecules tobe delivered. These materials are preferably polymeric materials.Materials can be selected for use as reservoir caps to give a variety ofdegradation rates, dissolution rates, or permeabilities to enable therelease of PTH molecules from different reservoirs at different timesand, in some cases, different rates. To obtain different release times(amounts of release time delay), caps can be formed of differentpolymers (e.g., that dissolve at varying rates), the same polymer withdifferent degrees of crosslinking, or a UV polymerizable polymer. In thelatter case, varying the exposure of this polymer to UV light results invarying degrees of crosslinking and gives the cap material differentdiffusion properties or degradation or dissolution rates. Another way toobtain different release times is by using one polymer, but varying thethickness of that polymer. Thicker films of some polymers result indelayed release time. Any combination of polymer, degree ofcrosslinking, or polymer thickness can be modified to obtain a specificrelease time or rate.

The layered release system technique described above for use inachieving a pulsatile PTH release profile advantageously andsurprisingly has been found to aid in avoiding undesirable phenomenaduring release (e.g., aggregation, precipitation of PTH). It was foundthat when trying to release a solution of PTH at a low pH (e.g., pH 3)through a tiny reservoir opening (e.g., a square having 50 micron sides)and into a physiological solution (pH 7), the PTH could precipitate andblock the reservoir opening. While not being bound by any theory, it isbelieved that this phenomena was due to the salts (e.g., MW ˜60) in thePTH solution diffusing into the physiological solution at a rate thatexceeded the rate of diffusion of the PTH (e.g., MW ˜4000) due, forexample, to the molecular weight (MW) dependence of diffusion rate, tosuch an extent that the pH of the PTH solution increased to a pointexceeding that required to keep the PTH in solution. (For example, at pH3, the PTH has a solubility of about 100 μg/ml and at pH 7, the PTH hasa solubility of about 20 μg/ml.)

By varying the concentration of the PTH to account for the massdiffusion rate differences, precipitation of the PTH can be avoided,e.g., to keep the PTH concentration (and/or pH) at the reservoir openingsufficiently low. It is believed that the same technique could be usedto prevent aggregation/precipitation of other proteins or peptidesreleased from a micro-reservoir system. For example, the release systemin a reservoir could comprise layers of different drug content and/orexcipient which could effect release rates and localized drugconcentrations within and adjacent the reservoir during release. In oneembodiment, the reservoir release system comprises alternating layers ofdrug and non-drug materials. FIG. 5 illustrates device 50 comprisingsubstrate 52 having reservoirs covered by reservoir caps 54 andcontaining a release system that consists of PTH-containing layers 56which are alternated with excipient layers 58. In another embodiment,the layers comprises different concentrations of PTH, in accordance withthe varying diffusion distances (and varying cross-sectional areas forreservoirs having tapered walls) in the reservoir. In such layeringtechniques, a solid fill is needed, for example, where layers comprisesa matrix material (e.g., in the form of a sol or gel) having drugdispersed therein. In one embodiment, the matrix material is awater-soluble, inert polymer, such as polyethylene glycol (PEG), whichis solid at 37° C.

Sensors

In an optional embodiment, the microchip device includes a sensor orsensing component. For example, the sensor or sensing component can belocated in a reservoir or can be attached to the device substrate. Thesensor can operably communicate with the device, e.g., through amicroprocessor, to control or modify the drug release variables,including dosage amount and frequency, time of release, effective rateof release, selection of drug or drug combination, and the like. The“sensing component” includes a component utilized in measuring oranalyzing the presence, absence, or change in a chemical or ionicspecies, energy, or one or more physical properties (e.g., pH,pressure). Types of sensors include biosensors, chemical sensors,physical sensors, or optical sensors. Further examples of such sensorsand sensor components are described in PCT WO 01/64344. The sensor orsensing component detects (or not) the species or property at the siteof in vivo implantation (e.g., in a bodily fluid or tissue), and furthermay relay a signal to the microprocessor used for controlling releasefrom the microchip device, as detailed below. Such a signal couldprovide feedback on and/or finely control the release of parathyroidhormone.

In one embodiment, the sensor measures plasma calcium levels in thepatient and modulates release of PTH or other drugs in response to themeasured calcium level, and the amount of parathyroid hormone releasedfrom the microchip is dependent on the level of plasma calcium detectedby such a sensor. An example of a calcium sensor is described in Van DenBurg, et al., “An ISFET-Based Calcium Sensor Using a PhotopolymerizedPolysiloxane Membrane,” Sensors & Actuators B, vol. 4, pp. 235-38(1991).

The microchip device may also factor in other information in determiningthe amount and timing of PTH release. For example, bone density andhydroxyproline levels in the urine may be clinical indicators for PTHtreatment, and the presence of hyperthyroidism or fluctuation in calciumhomeostasis may relate to the increased calcium levels detected. Suchinformation can be transmitted to the microchip device, preferablywirelessly, from other sensors and/or from a physician inputting theinformation derived, for example, from diagnostic tests performed on thepatient.

There are several different options for receiving and analyzing dataobtained with devices located in the microchip devices. Active microchipdevices may be controlled by local microprocessors or remote control.Biosensor information may provide input to the controller to determinethe time and type of activation automatically, with human intervention,or a combination thereof.

Typically, the operation of the microchip system will be controlled byan on-board (i.e. within the package) microprocessor. The output signalfrom the device, after conditioning by suitable circuitry if needed,will be acquired by the microprocessor. After analysis and processing,the output signal can be stored in a writeable computer memory chip,and/or can be sent (e.g., wirelessly) to a remote location away from themicrochip. Power can be supplied to the microchip system locally by amicrobattery or remotely by wireless transmission.

In one embodiment, the microchip device includes one or more biosensors(which may be sealed in reservoirs until needed for use) that arecapable of detecting and/or measuring signals within the body of apatient. As used herein, the term “biosensor” includes sensing devicesthat transduce the chemical potential of an analyte of interest into anelectrical signal (e.g., an ion selective field effect transistor orISFET), as well as electrodes that measure electrical signals directlyor indirectly (e.g., by converting a mechanical or thermal energy intoan electrical signal). For example, the biosensor may measure intrinsicelectrical signals (EKG, EEG, or other neural signals), pressure,temperature, pH, or loads on tissue structures at various in vivolocations. The electrical signal from the biosensor can then bemeasured, for example by a microprocessor/controller, which then cantransmit the information to a remote controller, another localcontroller, or both. For example, the system can be used to relay orrecord information on the patient's vital signs or the implantenvironment, such as drug concentration.

One embodiment of an implantable active-release microchip device fordelivery of PTH is illustrated in FIG. 1. It shows, in a perspectiveview, microchip device 10, which includes substrate/reservoir portion 12in a biocompatible package 14, such as a titanium encasement. Thepackage 14 further includes battery 16 and other device electronics.FIG. 1 also shows a close-up, in a perspective and partialcross-sectional view, of a portion of substrate/reservoir portion 12.The close-up illustrates two reservoirs 22 a and 22 b in substrate 20,which contain release system 26 comprising parathyroid hormone. Thereservoirs 22 a and 22 b are covered by anodic reservoir caps 24 a and24 b, respectively, which could be opened by an electrochemicaldegradation mechanism upon application of an electric potential betweena cathode 25 and the anode reservoir caps.

Another embodiment of an implantable active-release microchip device fordelivery of PTH is illustrated in FIG. 2. As in FIG. 1, it shows, in aperspective view, microchip device 10, which includessubstrate/reservoir portion 12 in a biocompatible package 14, such as atitanium encasement. The package 14 further includes battery 16 andother device electronics. The close-up view in FIG. 2 also shows, in aperspective and partial cross-sectional view, a portion ofsubstrate/reservoir portion 12, illustrating two reservoirs 28 and 32 insubstrate 20, which contain release system 26 comprising parathyroidhormone. In this embodiment, the reservoirs 28 and 32 are covered byreservoir caps 28 a and 32 a, respectively. Reservoir cap 28 a iselectrically connected to electrical input lead 28 b and to electricaloutput lead 28 c, and reservoir cap 32 a is electrically connected toelectrical input lead 32 b and to electrical output lead 32 c. Thesereservoir caps could be opened via a thermal rupturing mechanism bypassing an electric current through the caps in an amount effective tolocally heat the cap material and rupture the reservoir cap.

II. Methods of Making the Medical Devices

Methods for making the substrate, reservoirs, and reservoiropening/activation components are described for example in U.S. Pat. No.5,797,898; U.S. Pat. No. 6,123,861; U.S. Patent Application PublicationNo. 2002/0107470; U.S. Patent Application Publication No. 2002/0151776,and U.S. Patent Application Publication No. 2002/0183721, as well asU.S. Pat. No. 7,455,667, which are hereby incorporated by reference intheir entirety. In one embodiment, a MEMS technique is used to make thesubstrate, reservoirs, and reservoir caps. In another embodiment,standard machining techniques, such as drilling or laser machining areused to make the substrate and reservoirs.

In yet another embodiment, soft lithography, microcontact printing, orthe like is used. For example, these techniques can be useful forforming leads and reservoir caps on non-planar substrates. See, e.g.,U.S. Pat. No. 6,180,239; No. 5,951,881; No. 6,355,198; and No.6,518,168.

In one embodiment, the assembly of a complete microchip drug deliverydevice involves a number of packaging steps, including (1) attachment ofelectrical leads to the substrate, (2) filling of the reservoirs with arelease system comprising PTH, (3) sealing the reservoirs, (4)integration with electronic components and power sources, and (5)placing the microchip(s) and associated components within a singlebiocompatible enclosure or “package.” The package optionally may beconformally coated with parylene or an inert ceramic material (see e.g.,U.S. Patent Application Publication No. 2002/0187260). In someembodiments, insulating or dielectric materials are deposited over thereservoir cap, leads, or entire surface of the device by methods such aschemical vapor deposition (CVD), electron or ion beam evaporation,sputtering, or spin coating to protect the device or enhancebiostability/biocompatibility. Examples of such materials includeoxides, nitrides, carbides, diamond or diamond-like materials, orfluorocarbon films. Methods for assembling, sealing, and packagingmicrochip chemical delivery devices useful herein are described, forexample, in U.S. Pat. No. 6,123,861, U.S. Patent Application PublicationNo. 2002/0119176 and No. 2003/0010808, which are expressly incorporatedherein by reference.

In one embodiment, the step of reservoir sealing and the step offormation of a reservoir cap over the reservoir opening can be combined.This is particularly useful for devices in which the reservoirs arefilled and released from the same side, for example, in embodimentswhere the reservoirs are formed in a substrate without penetratingthrough the entire thickness of the substrate. In an alternativeembodiment, the reservoir is filled from an opening in the end of thereservoir distal the reservoir cap, and then this opening is permanentlysealed.

III. Uses of the Medical Devices

The microchip devices and release methods described herein can be usedto deliver (i.e., administer) parathyroid hormone to a patient for avariety of treatments. For example, the devices and methods can be usedto reduce the incidence of bone fractures, defects, and disorders whichresult from weakened bones due to as osteoporosis, osteoarthritis,Paget's disease, osteohalisteresis, osteomalacia, bone loss resultingfrom multiple myeloma and other forms of cancer, bone loss resultingfrom side effects of other medical treatment (such as steroids), andage-related loss of bone mass. In addition, the microchip device couldbe used for strengthening a bone graft, for treating prosthetic ingrowthsuch as promoting bone ingrowth into a bone prosthesis, for treating abone fracture, or for treating childhood idiopathic bone loss in achild.

As used herein, the term “patient” refers to a living vertebrate animalsuch as a mammal (e.g., human) in need of treatment, i.e., in need ofbone repair, augmentation, or replacement. The term “treatment” refersto (1) providing a patient with an amount of a substance sufficient toact prophylactically to prevent the development of a weakened and/orunhealthy state; (2) providing a patient with a sufficient amount of asubstance so as to alleviate or eliminate a disease state and/or thesymptoms of a disease state, and a weakened and/or unhealthy state; (3)providing a patient with an amount of a substance sufficient to promotebone formation; or (4) providing combinations of such substances.

In one embodiment, the microchip device is implanted into the patientfor long-term delivery of PTH, alone or in combination with other drugs.“Long term” refers to release over an extended period (e.g., between 1week and 3 years, between 6 weeks and 2 years, between 3 months and 1year, etc.). The microchip device can be implanted in vivo usingstandard surgical or minimally invasive implantation techniques, e.g.,via a catheter, at any suitable site. Preferred sites includesubcutaneous pectoral or abdominal sites. Depending upon the particularadministration route or implantation site, the microchip device can beused for local, regional, or systemic delivery of PTH.

In one embodiment, the medical device is adapted to deliver the PTH bythe vaginal route. The medical device could use active release or couldrely solely on passive release to deliver the PTH. A particularadvantage of using the vaginal route of administration for deliveringPTH is that deployment of the device is not surgical. No implantationprocedure is necessary; rather the device is manually inserted into thevagina of the patient, not unlike a tampon or conventional vaginal ringdevice. In one embodiment, the device would be designed for morefrequent replacement than would be desirable for a subcutaneous device.In such an embodiment, the device would not need to hold as much PTH asthe device for subcutaneous implantation. In an active embodiment, thecontrol electronics and power source could also be simplified, therebyreducing the cost of the device. In one embodiment, the microchip devicecould be made to be very small and release daily doses of PTH for one ortwo months, after which time the device could be removed and replacedwith a new one. If appropriate, treatment could be halted immediately atany time by simply removing the device.

In one embodiment, the microchip device includes or is combined with apolymeric (e.g., medical grade silicone rubber) body, such as a strip-,rod-, or torus-shaped device. The body can be, for example, in the formof a vaginal ring-like device (see e.g., U.S. Patent ApplicationPublication No. 20020161352, U.S. Pat. No. 4,822,616, and U.S. Pat. No.4,012,496, for description of vaginal rings that can be modified for useherein). A patient or a caregiver can manually place the device into thevagina, where the device remains secured in place by contact (e.g.,frictional engagement) with the vaginal walls. In one embodiment, thevaginal ring device could include a polymeric coating that isbioadhesive to mucosal surfaces. Preferably no suturing or other morepermanent securing means would be required. In one technique, thevaginal ring/microchip device could include an expandable portion thatexpands upon insertion to enhance the frictional engagement with thevaginal walls. In another technique, the vaginal ring/microchip deviceis selected to have a size appropriate for a particular patient.

In yet another embodiment, an array of discrete microreservoirs arefabricated directly into a vaginal ring body (which serves as thesubstrate), as illustrated in FIGS. 6-7. The substrate is (integralwith) the attachment body. These figures show device 60 havingring-shaped body 62 in which a plurality of reservoirs containing a PTHformulation 66 are located. The reservoirs are sealed by (generic)reservoir caps 64. The reservoir caps may be opened by any of a numberof passive or active techniques described herein. Active control meanscan be embedded (e.g., within a compartment) in the ring-shaped body.The body can be a multilayer structure, for example it could have arigid core portion and a soft polymeric shell.

In a preferred embodiment, the drug-release side of the microchip deviceis positioned toward and in contact with the mucosal tissues of thevaginal wall. This facilitates transport of the drug from a reservoir,upon opening, to moist vaginal tissues, enabling the drug to diffuseinto the capillaries and other small blood vessels in the tissue, forsystemic delivery. Accordingly, in one embodiment of the PTH formulationfor vaginal administration, the PTH composition is formulated with apenetration enhancer or absorption promoter to enable such penetration,absorption, transfer or transport through the mucosa.

Once the microchip device is placed at the site that PTH delivery (i.e.release) is desired, the PTH can be controllably released from one ormore of the reservoirs, either actively or passively, in apharmaceutically effective amount at the desired dosing schedule. Theterm “pharmaceutically effective” refers to that amount which effectsthe formation and differentiation of bone.

Generally, each reservoir is loaded with between about 10 and about 300μg of parathyroid hormone. In a preferred therapy, the microchip devicedelivers daily doses (pulses) of 20 μg/day of PTH (1-34) for one year,in order to grow bone, to restore lost bone mass.

The width (i.e., duration) of each pulse dose of PTH is selected to be atherapeutically effective period. In one embodiment, the duration ofeach pulse is less than four hours (e.g., less than three hours, lessthan two hours, less than one hour).

In a typical treatment method, the patient would first receive PTH byinjection for the first one or two months of therapy to ensure that thepatient experiences no adverse reactions (e.g., hypercalcemia) to thePTH treatment. Once it has been established that the patient isaccepting treatment with adverse reaction, then the microchip device forPTH delivery would be implanted into the patient. The microchip devicewould then provide administration of PTH, obviating the need forinjections going forward. In one embodiment, a single microchip deviceprovides least all of the PTH doses required over the course of therapy.For example, the device could contain enough PTH to provide daily dosesfor between about 10 months and about 12 months.

After the PTH treatment regimen is completed (e.g., after about oneyear), a treatment with one or more anti-resorptive agents is typicallybegun. For example, the treatment could include daily doses of a chronicbone loss inhibitor, for up to five years. Optionally, the same devicefurther provides some or all of the doses of anti-resorptive agent. Inother methods, the PTH is administered from the implanted microchipdevice, and the anti-resorptive agent is administered by another routesuitable for the selected anti-resorptive agent, such as orally or byparental injection.

In one embodiment, which could be implanted, a single, non-refillablemicrochip device is provided with at least a year's supply of PTH fordelivery. For example, the microchip device could have a substrateprovided with a 400-reservoir array, with each reservoir containing asingle dose, e.g., about 20 μg PTH (1-34) or about 100 to 200 μg PTH(1-84) in a suitable formulation.

For example, in an active-release embodiment, the microchip device canbe controlled by a pre-programmed microprocessor to open a one or aportion of the reservoirs intermittently (that is, a different one ormore reservoirs after each period) to effect release intermittently,e.g., in a pulsatile manner. In other variations, the microprocessor(and thus release) is controlled by a sensor, e.g., a biosensor, or byremote control.

In one embodiment of a passive release microchip device, the PTH can becontrollably released using reservoir caps formed of a biodegradablematerial (e.g., a polymer, such as PLGA). Release times can becontrolled and varied by altering the thickness of the reservoir cap,the composition of the reservoir cap (e.g., degree of crosslinking,etc.), or both.

In other embodiments, another drug is released before, simultaneouslywith, or following one or more releases of PTH. For simultaneousrelease, the other drug can be contained in the same reservoirs thatcontain the PTH or the other drug can be contained in one or moreseparate reservoirs. The other drug can be controllably released in acontinuous or intermittent manner. For example, PTH and raloxifene maybe administered sequentially, concurrently, or simultaneously as asingle composition to the patient. If administered sequentially, theperiod between the administration of PTH and raloxifene will typicallybe one week to one year, and optimally, one week to six months. In apreferred administration scheme, the patient will, after administrationof PTH, with or without raloxifene, be administered raloxifene aftercessation of administration of PTH.

In one embodiment, the PTH is released intermittently from the microchipdevice during a period between 6 and 24 months, and then once PTHadministration has been completely, a bone resorption inhibitor isreleased during a period between about 6 and 36 months.

Methods of using microchip devices for controlled release of drug andother molecules is further described in U.S. Pat. No. 5,797,898, No.6,123,861, No. 6,551,838, No. 6,491,666, and No. 6,527,762, and U.S.Patent Application Publications No. 2002/0138067, No. 2002/0072784, No.2002/0151776, and No. 2002/0107470.

Publications cited herein and the materials for which they are cited arespecifically incorporated by reference. Modifications and variations ofthe methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

1. An implantable device for the extended, controlled delivery ofparathyroid hormone to a patient in need thereof comprising: a substratehaving a plurality of discrete reservoirs therein; a release systemcontained in each of the reservoirs, wherein the release systemcomprises parathyroid hormone in a dried or lyophilized form; and acontrol means for selectively releasing a pharmaceutically effectiveamount of the parathyroid hormone from the reservoirs in dailyintermittent doses of between about 10 and 300 μg.
 2. The device ofclaim 1, which is adapted to release the parathyroid hormone once dailyover a period of at least six months.
 3. The device of claim 1, whereinthe parathyroid hormone is recombinantly synthesized.
 4. The device ofclaim 1, wherein the parathyroid hormone is a fragment of the completehuman hormone that promotes bone growth responsible for bone growthpromotion or an analog thereof in which the amino acid sequence ismodified yet retains its bone growth promotion property.
 5. The deviceof claim 1, wherein the parathyroid hormone consists essentially of hPTH1-34, hPTH 1-38, or hPTH 1-28.
 6. The device of claim 1, wherein thecontrol means comprises (i) reservoir caps covering the release systemof the discrete reservoirs and (ii) a means for actively disintegratingthe reservoir caps.
 7. The device of claim 6, wherein the means foractively disintegrating comprises a power source for passing an electriccurrent or potential through the reservoir caps.
 8. The device of claim7, wherein the means for actively disintegrating the reservoir capsincludes electrical input and output leads electrically connected toeach of the reservoirs caps, the input and output leads and thereservoir caps being constructed to provide that the reservoir capsrupture by electrothermal ablation upon said passing of an electriccurrent through the reservoir caps.
 9. An implantable device forcontrolled delivery of parathyroid hormone to a patient in need thereofcomprising: a substrate having a plurality of discrete reservoirs; aquantity of parathyroid hormone contained in each of the reservoirs; aplurality of reservoir caps separating said quantity of parathyroidhormone from an environment outside of the reservoirs, and preventingthe parathyroid hormone from being released from the implantable device;and means for disintegrating one or more of the discrete reservoir capsto release the parathyroid hormone from one or more of the reservoirs,wherein each of said reservoir caps comprise a multi-layer metalstructure.
 10. The device of claim 9, wherein the multi-layer structurecomprises platinum and titanium.
 11. The device of claim 9, wherein theparathyroid hormone in a dried or lyophilized form.
 12. The device ofclaim 9, which includes a control means for selectively releasing apharmaceutically effective amount of the parathyroid hormone from thereservoirs in daily intermittent doses of between about 10 and 300 μg.13. The device of claim 9, which is adapted to release the parathyroidhormone once daily over a period of at least six months.
 14. The deviceof claim 9, wherein the parathyroid hormone is recombinantlysynthesized.
 15. The device of claim 9, wherein the parathyroid hormoneis a fragment of the complete human hormone that promotes bone growthresponsible for bone growth promotion or an analog thereof in which theamino acid sequence is modified yet retains its bone growth promotionproperty.
 16. The device of claim 9, wherein the parathyroid hormoneconsists essentially of hPTH 1-34, hPTH 1-38, or hPTH 1-28.
 17. Thedevice of claim 9, wherein the means for actively disintegratingcomprises a power source and electrical input and output leadselectrically connected to each of the reservoirs caps, the input andoutput leads and the reservoir caps being constructed to provide thatthe reservoir caps rupture by electrothermal ablation upon said passingof an electric current through the reservoir caps.